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Significance

Mice can reduce their body temperature and metabolic rate and enter torpor when they are subjected to cold, calorie deprivation, or administration of some metabolic inhibitors. Here we show that administration of pyruvate, a key metabolic intermediate and substrate for gluconeogenesis, induces torpor in obese mice, resulting in marked hypothermia, decreased activity, and decreased metabolic rate. This is dependent on adenosine signaling and on changes in key brain metabolites, including GABA. Lean mice are protected from pyruvate-induced torpor by activating their brown adipose tissue. Understanding this pathway can help provide new approaches for inducing a hypometabolic state in mammals, which could be beneficial in states of food deprivation or ischemia–reperfusion injury and for organ preservation in surgical situations.

Abstract

Mice subjected to cold or caloric deprivation can reduce body temperature and metabolic rate and enter a state of torpor. Here we show that administration of pyruvate, an energy-rich metabolic intermediate, can induce torpor in mice with diet-induced or genetic obesity. This is associated with marked hypothermia, decreased activity, and decreased metabolic rate. The drop in body temperature correlates with the degree of obesity and is blunted by housing mice at thermoneutrality. Induction of torpor by pyruvate in obese mice relies on adenosine signaling and is accompanied by changes in brain levels of hexose bisphosphate and GABA as detected by mass spectroscopy-based imaging. Pyruvate does not induce torpor in lean mice but results in the activation of brown adipose tissue (BAT) with an increase in the level of uncoupling protein-1 (UCP1). Denervation of BAT in lean mice blocks this increase in UCP1 and allows the pyruvate-induced torpor phenotype. Thus, pyruvate administration induces torpor in obese mice by pathways involving adenosine and GABA signaling and a failure of normal activation of BAT.

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